In mammals, cellular communication is mediated by cell-surface molecules, or receptors, that are present on the membrane surface of all mammalian cells. Cell-surface molecules are activated by binding a molecule outside the cell. Interaction with the molecule causes the receptor to change, move, realign, reorganize and redistribute on the cell surface and activate the cell. The molecule outside the cell can be a cell-surface molecule on another cell, or an unattached independent binding molecule.
Binding or otherwise interacting with the external molecule results in dimerization or oligomerization of the receptor on the cell surface, which in turn initiates a cascade of biochemical signals that are relayed to molecules within the cell. Molecules within the cell then convey directions for other events, the most common of which is a change in transcription and expression of a gene known to be “downstream” of the receptor in a pathway. After expression of the genes that have been “turned on”, more events and consequences occur in the cell. These consequences and events are manifested in mammals in conditions and states of the cell's tissue source. A simple condition is healthy tissue. A more complicated condition is diseased tissue. It is foundational that basic scientific research done for development of medical advances is attempting to address how to alter cell activity in diseased tissue in order to direct the tissue to heal, and the disease to reverse.
Structural characterization of receptor associations during receptor-mediated cell activation has been studied in a number of labs. See e.g., (R. J. Mannix et al., Nature Nanotechnology 3, 36 (Jan., 2008); A. S. Harding, J. F. Hancock, Trends in Cell Biology 18, 364 (Aug., 2008); T. Boldog, S. Grimme, M. Li, S. G. Sligar, G. L. Hazelbauer, Proceedings of the National Academy of Sciences 103, 11509 (Aug. 1, 2006); X. Zhang, J. Gureasko, K. Shen, P. A. Cole, J. Kuriyan, Cell 125, 1137 (2006)).
On a micrometer scale, protein interactions involving multiple protein complexes is critical to cell signaling, particularly in the juxtacrine type signaling found in adhesion junctions. See e.g. (D. G. Drubin, W. J. Nelson, Cell 84, 335 (Feb. 9, 1996)), the neuronal synapse (V. N. Murthy, P. De Camilli, Annual Review of Neuroscience 26, 701 (2003)), and the immunological synapse (C. R. F. Monks, B. A. Freiberg, H. Kupfer, N. Sciaky, A. Kupfer, Nature 395, 82 (Sep. 3, 1998)).
Deconstructing what cell-surface signaling molecules do after binding an ligand is a challenge because of the chemical heterogeneity of the cell membrane and the complexity of effecting cell-cell contact in an in vitro system. However, the challenge may be worth addressing. Future directions for diagnosis and treatment of many complicated and illusive diseases, the hallmark of which is cancer, seem to point towards patient-specific targeting of a disease condition.
While genetic screening and protein expression profiling can yield information, they fall short of elucidating in vivo receptor function and behavior. These current techniques are usually indirect by design with respect to activation on the cell surface, and cannot be expected to perform beyond their limits, especially with regard to the challenge of decoding the complex events that activate the cell from a receptor at the surface. There is a need for assays that convey accurate information about the behavior of cells derived from tissue exhibiting the condition.